Considering the potential side effects, deciding whether or not to treat your dog’s Cushing’s disease with a pharmaceutical drug is stressful.
Pharmaceutical Choices for Cushing’s Treatment
Pharmaceutical options include:
The current treatment of choice for pituitary-dependent Cushing’s is chemotherapy with op-DDD (mitotane, Lysodren®).
Mitotane is derived from the insecticide DDT.
The drug causes severe and progressive necrosis or death of certain parts of the adrenal gland.
Basically, the drug eats away at the adrenal gland.
Normal dogs for some unknown reason are clinically quite resistant to the effects of the drug.
Prior to initiation of mitotane, the clinical signs should be consistent with a diagnosis of hyperadrenocorticism and the diagnosis should be confirmed.
Dogs should be systemically normal with a good to excellent appetite. Mitotane should never be administered to animals that are not eating well.
Since Mitotane selectively destroys the adrenal gland, the risk of too much destruction should be considered and is always a possibility.
Prednisone is not usually administered concurrently, but a small supply of prednisone should be made available to the owner in case of an emergency.
When too much adrenal destruction occurs, prednisone may be necessary to ameliorate the clinical manifestations.
When adrenal destruction occurs, the event is called iatrogenic addisonians.
Mitotane should be administered for up to 10 days, until water consumption decreases to <100 mL/kg/day, or until a decreased appetite, depression, diarrhea, or vomiting are observed.
At this point, the dog should be reevaluated and an ACTH stimulation test performed.
Prednisone treatment (0.1 to 0.2 mg/kg) should be initiated in patients that are showing clinical signs of too little cortisol, until the results of the ACTH stimulation test are known.
In patients who are not polydipsic, patients in which water consumption cannot be monitored, and patients in which polydipsia is due to another underlying disease (eg, diabetes mellitus), mitotane should be administered for a maximum of 5-7 days prior to testing.
The goal of treatment is to have both the pre- and post-cortisol measurement in the normal range.
Maintenance therapy (50 mg/kg q 7-10 days) is started once the ACTH stimulation test is adequately suppressed and prednisone therapy (if necessary) has been discontinued.
Failure to use maintenance therapy will result in regrowth of the adrenal cortex and recurrence of clinical signs.
Efficacy of maintenance therapy is monitored by an ACTH stimulation test in 1 month and then every 3 to 4 months thereafter.
Reasons for treatment failure include the following:
- Incorrect diagnosis
- Presence of an adrenal tumor although some adrenal tumors will respond
- Latrogenic Cushing’s due to prednisone administration
- Requirement for a higher dose or duration of treatment
Side effects of mitotane can be severe and include:
- Gastric irritation
- Addisonian crisis (drug eats away too much adrenal tissue)
- Occasionally neurologic signs
- Inability to distinguish drug intolerance versus Addisonian crisis
Mean survival time of 200 dogs treated with mitotane was 2.2 years (range 10 days to 8.2 years).
The advantage of Mitotane is, in the majority of cases, mitotane produces excellent control of clinical signs associated with Cushing’s.
Mitotane has disadvantages as well. Destroying the tissue of the adrenal gland is not definitive therapy for pituitary-dependent Cushing’s.
In dogs that fail to respond to mitotane or dogs that do not tolerate the drug, the next choice of therapy is Trilostane.
Trilostane is a synthetic hormonally inactive steroid analog, which is a competitive inhibitor of the 3 beta-hydroxysteroid dehydrogenase system.
The drug blocks production of a number of adrenal steroids including cortisol and aldosterone.
Trilostane is rapidly absorbed orally although suppression of plasma cortisol concentrations is short lived.
Trilostane is well tolerated by dogs and is reportedly effective in controlling polyuria and polydipsia in 70% of cases, and dermatologic changes in approximately 60% of dogs.
Trilostane is well tolerated in most dogs.
Adverse effects that have been reported include diarrhea, vomiting, and lethargy in 63% of dogs, which is usually mild and self-limiting.
Advantages of Trilostane
Experience from Europe suggests trilostane is an effective and safe treatment for canine pituitary-dependent Cushing’s.
Trilostane reportedly has a lower incidence of side effects compared with mitotane.
Disadvantages of Trilostane
The major disadvantage of Trilostane therapy is that it is not definitive therapy for PDH.
Side Effects of Trilostane
Commonly reported adverse reactions include:
- Loss of appetite
Less common but potentially fatal reactions include:
- Hemorrhagic diarrhea
- Addisonian crisis
- Adrenal death
Ketoconazole is an orally active antifungal agent commonly used in veterinary medicine to treat fungal infections.
Ketoconazole does not result in good long-term control of Cushing’s disease.
A dose of 30 mg/kg every 12 hours results in a rapid reduction of serum cortisol concentrations in most animals.
Signs of toxicity are uncommon but include anorexia and vomiting.
The disadvantages of Ketoconazole include:
- Need for daily medication
- Poor long-term control in many cases
Ketoconazole is most useful for the palliative therapy of metastatic adrenal tumors and for presurgical stabilization of operable adrenal tumors.
L-deprenyl is a selective monoamine oxidase type B inhibitor, which increases CNS dopamine concentrations.
Treatment with L-deprenyl has recently been reported to be effective in less than 20% of dogs with PDH.
Surgical Treatment of Adrenocortical Tumors
In the unfortunate circumstance of an adrenal tumor, treatment involves either surgical resection of the tumor or medical therapy with mitotane, trilostane, or ketoconazole.
Removal of the adrenal gland should be reserved for patients without extensive tumor invasion or metastasis.
Abdominal ultrasound can assist in planning the surgery.
After surgically removing the diseased gland, the normal adrenal gland tissue will be atrophic and glucocorticoid, and sometimes mineralocorticoid supplementation is necessary in the perioperative and postoperative period.
The prognosis for adrenocortical tumors without metastatic disease that survive the initial perioperative period is good.
In one study, 80% of dogs survived the perioperative period.
Some dogs with inoperable tumors or metastatic disease may respond to medical treatment with high doses of op-DDD (mitotane).
Mitotane is often successful in controlling clinical signs and in some cases may also result in tumor shrinkage.